Center for GI Cancers CME Series: Colorectal Liver Metastases

Transcript

• 00:00Twenty twenty six CME series.
• 00:04Today is March nineteenth. We
• 00:06are in the middle of,
• 00:09colorectal
• 00:10cancer awareness month. And so,
• 00:13this event tonight is gonna
• 00:15focus on,
• 00:17colorectal cancer, specifically,
• 00:20the management options for patients
• 00:22with, colorectal liver metastases.
• 00:25I'm Jeremy Kortmansky.
• 00:27I'm,
• 00:28a associate professor
• 00:30of medicine and GI medical
• 00:32oncology
• 00:33at Yale.
• 00:34I am joined by doctor
• 00:37Khan, a surgical oncologist and
• 00:39chief of the hepatobiliary
• 00:41surgery service,
• 00:43doctor
• 00:43Madoff, an interventional radiologist and
• 00:46chief of the interventional radiology
• 00:48service,
• 00:49and, doctor Kevin Du, a
• 00:51radiation oncologist.
• 00:55And so I will,
• 00:58get us going,
• 01:00hopefully.
• 01:02Colo as a background, colorectal
• 01:04cancer is the third leading
• 01:06cause of cancer in the
• 01:07United States and the second
• 01:09leading cause of cancer death.
• 01:11It's estimated there'll be about
• 01:13a hundred and fifty nine
• 01:15thousand,
• 01:16new cases in the US
• 01:17in twenty twenty six
• 01:19with more than fifty five
• 01:21thousand deaths.
• 01:22Nearly a third of these
• 01:23cases are rectal cancer.
• 01:26In men under fifty,
• 01:29colorectal cancer is now the
• 01:30number one cause of cancer
• 01:32related mortality.
• 01:34Recent trends that we're seeing
• 01:36is that,
• 01:37the number of incidence in
• 01:40patients over sixty five years
• 01:42of age is decreasing,
• 01:44but is rapidly increasing in
• 01:46patients who are under fifty
• 01:47years old at a rate
• 01:48of three percent per year.
• 01:51And patients under sixty five
• 01:52now represent
• 01:54forty five percent of all
• 01:55new cases.
• 01:57Seventy five percent of patients
• 01:59under fifty present with advanced
• 02:01disease.
• 02:04In this group of patients,
• 02:06forty to fifty percent will
• 02:08develop liver metastases.
• 02:11Conventional systemic chemotherapy
• 02:13alone has limited efficacy
• 02:16with five year overall survival
• 02:18less than fourteen percent
• 02:20with modern regimens,
• 02:22and only a two percent,
• 02:24having durable response at five
• 02:26years.
• 02:28Sightedness matters. It's something we
• 02:30talk about often with left
• 02:31sided tumors having a higher
• 02:33incidence
• 02:34of liver metastases
• 02:35versus right sided,
• 02:37but right sided tumors and
• 02:39rectal,
• 02:40cancers having a worse survival.
• 02:43This is likely related to
• 02:44biology.
• 02:46Right sided tumors have more
• 02:48KRAS mutations,
• 02:49BRAF mutations,
• 02:51and microsatellite
• 02:52instability.
• 02:54Left sided tumors are more
• 02:55often KRAS wild type and
• 02:58driven by EGFR mediated pathways.
• 03:03Looking at prognosis
• 03:04based on these factors,
• 03:06patients with left sided KRAS
• 03:08wild type tumors have the
• 03:10best prognosis,
• 03:12whereas those with right sided
• 03:13and KRAS mutated tumors have
• 03:15the worst prognosis.
• 03:19Aggressive local management of liver
• 03:21metastases
• 03:22can improve five year overall
• 03:23survival and cure some patients.
• 03:26The risk of relapse remains
• 03:28high, and there are multiple
• 03:31risk factors that can be
• 03:32attributed to that,
• 03:34risk of relapse,
• 03:35including elevated CEA,
• 03:38the number of liver metastases,
• 03:40large liver lesions, bilateral involvement,
• 03:43the stage of the primary
• 03:45tumor,
• 03:46regional nodal involvement,
• 03:48a short disease free interval
• 03:50or synchronous metastases,
• 03:52and tumor biology.
• 03:57As I said, I am
• 03:58fortunate to be,
• 04:00joined by experts in all
• 04:02aspects
• 04:04of management of patients with
• 04:06liver metastases,
• 04:08and I will,
• 04:09start by,
• 04:11turning it over to doctor
• 04:13Khan to talk to us
• 04:14about surgery.
• 04:21Excellent. Thanks, doctor Kordomanski,
• 04:24for getting us started. I'm
• 04:25really excited to to do
• 04:26this session with yourself and
• 04:28doctor Madoff and doctor Du,
• 04:30and it's great to work
• 04:31at Yale with such
• 04:33wonderful experts.
• 04:36So, you know, so I'm
• 04:37the surgical oncologist in the
• 04:38group. So,
• 04:40I will be focusing on,
• 04:42this this part of the
• 04:43talk,
• 04:44discussing the very basic surgical
• 04:46approaches to the management of
• 04:48colorectal cancer
• 04:49liver metastases.
• 04:52This is a slide, similar
• 04:53to doctor Hartmansky's. It's probably
• 04:55a year outdated compared to
• 04:56his slides, but colorectal cancer
• 04:58is
• 04:59a common cause of diagnosis,
• 05:01of cancer in the United
• 05:03States affecting female and male
• 05:05patients,
• 05:06regularly.
• 05:08It's one of the leading
• 05:09cause of cancer deaths as
• 05:10well in the United States.
• 05:12But specifically, when we talk
• 05:13about colorectal cancer, it's important
• 05:15to understand the that metastasis
• 05:17is the leading cause of
• 05:19cancer specific deaths.
• 05:22Over fifty percent of patients
• 05:24with colorectal cancer will develop
• 05:25liver metastases at some point
• 05:27in their diagnosis either at
• 05:28the time of the diagnosis
• 05:30or, at a later time.
• 05:33When someone has developed diagnosed
• 05:34with liver metastases at the
• 05:36time of the diagnosis of
• 05:37the colon cancer, this is
• 05:39referred to as synchronous metastases.
• 05:41And this effect, this is
• 05:43a diagnosed in twenty to
• 05:44thirty four percent of, of
• 05:46individuals with the new colon
• 05:48cancer diagnosis.
• 05:50However, the majority do present
• 05:51in a metachronous fashion, which
• 05:53means they're diagnosed
• 05:54at least six months after
• 05:56the index,
• 05:57diagnosis.
• 05:59Conventional systemic chemotherapy has seen
• 06:01great advances,
• 06:02over the last twenty five
• 06:04to thirty years.
• 06:05However, it, it has some
• 06:07limited efficacies,
• 06:09and I think we're gonna
• 06:09spend some time talking a
• 06:11bit more about what some,
• 06:12liver specific treatments,
• 06:15can,
• 06:15be an advantage for patients
• 06:17with the colon cancer, liver
• 06:19metastasis diagnosis.
• 06:21Five year survival, with just
• 06:23chemotherapy
• 06:24can be low,
• 06:26and oftentimes patients don't have
• 06:28a durable response at five
• 06:29years. So hence the thought
• 06:31about,
• 06:32other options.
• 06:33Before jumping ahead to what
• 06:35the surgical treatments may be
• 06:37for patients with colorectal cancer,
• 06:38I do wanna share,
• 06:40a patient,
• 06:41with you that we our
• 06:43Yale multidisciplinary
• 06:44team has taken care of
• 06:45here at, the Yale Cancer
• 06:47Center and Smile of Cancer
• 06:48Hospital,
• 06:49and this is a patient
• 06:50that's fifty seven years old,
• 06:53had a partial colectomy, meaning
• 06:54part of the colon was
• 06:55resected,
• 06:58and, for what's called a
• 06:59node one positive for a
• 07:01node positive colon cancer.
• 07:03That patient received,
• 07:04six cycles of chemotherapy,
• 07:08and,
• 07:09and then he has some
• 07:10relatively healthy individual.
• 07:14He was followed by our,
• 07:16one of our one of
• 07:17our SmileCare Centers by one
• 07:19of our very good medical
• 07:20oncologists and what was noted
• 07:21with the tumor marker surveillance
• 07:23and CEAs, the tumor marker
• 07:24surveillance
• 07:25was shown to be rising.
• 07:28And, hence, eventually, the patient
• 07:30was found to have a
• 07:32liver metastasis
• 07:33in the right liver,
• 07:35in the right medial liver.
• 07:36And,
• 07:37and then he was referred
• 07:39to our surgical oncology team
• 07:40in our as part of
• 07:41our multidisciplinary
• 07:42program,
• 07:43for what to do.
• 07:45And we went ahead and
• 07:46performed a liver resection, performed
• 07:48what's called the right hepatectomy,
• 07:50for this patient, and this
• 07:51is an example of what
• 07:52the,
• 07:53what the specimen looks like
• 07:55after it's removed from the
• 07:56body of the patient,
• 07:58on what's called a gross
• 07:59image.
• 08:02So
• 08:03with that,
• 08:04case presentation,
• 08:05in the background,
• 08:06here are some of the
• 08:07I wanted to talk use
• 08:08that as an opportunity to
• 08:09talk about some of the
• 08:10surgical options for colorectal cancer
• 08:12liver metastases.
• 08:13One option is a hepatectomy,
• 08:15which means, the portion of
• 08:17the cancer is removed,
• 08:19along with the portion of
• 08:19the liver.
• 08:21Sorry. The cancer is removed
• 08:22along with the portion of
• 08:23the liver. Microwave ablation, we
• 08:25have doctor Madoff here who's
• 08:26an a world expert, and
• 08:27I suspect expect he'll be
• 08:28talking about some of this
• 08:29as well too. It's something
• 08:30that some of the surgical
• 08:31oncologists we consider in our,
• 08:33surgical armamentarium.
• 08:35Hepatic Arterial Infusion Pump Placement,
• 08:37which we'll spend a little
• 08:38bit of time talking about,
• 08:39and tell you a little
• 08:40bit more about our hepaticartrial
• 08:42infusion,
• 08:43pump program.
• 08:45And liver transplant, we're not
• 08:46gonna talk too much about,
• 08:47but it is something that's
• 08:49starting to become as an
• 08:50emerging option,
• 08:51more so in Europe, than
• 08:53in the United States.
• 08:56In regards to a hepatectomy,
• 08:58so why would we do
• 08:59it? So, you know, anytime,
• 09:00patients and their family members
• 09:02see us in,
• 09:03our surgical oncology clinic, you
• 09:05know, one thing that, we
• 09:07have a discussion about is
• 09:08what is the best way
• 09:09we can help, the patient
• 09:11and their family member in
• 09:12this not just the short
• 09:13term, but in the long
• 09:14term.
• 09:15And this is, some data
• 09:17to support the benefit of
• 09:18doing a liver resection,
• 09:20for patients that develop a
• 09:22colorectal liver metastases
• 09:23because,
• 09:25a surgical approach for the
• 09:26resection of these tumors can
• 09:28provide,
• 09:30survival
• 09:31improvement and sometimes cure in
• 09:33patients.
• 09:34So and these are some
• 09:35series,
• 09:36that have been,
• 09:37very well published over the
• 09:39years.
• 09:41This picture shows
• 09:42some of the common types
• 09:44of liver sections that we
• 09:45perform.
• 09:46So the liver the way
• 09:47we look at it, the
• 09:48liver has eight different segments,
• 09:50and there's a right portion
• 09:51of the left liver and
• 09:52a left portion of the
• 09:53liver. And there's also a
• 09:54low called the caudate.
• 09:56These are some of the
• 09:57major liver sections that we
• 09:58performed,
• 09:59on figure in figure a.
• 10:02It shows what's called a
• 10:03right hepatectomy, which means,
• 10:05segments five, six, seven, and
• 10:06eight or the right portion
• 10:07of the liver,
• 10:08is resected.
• 10:10Picture b shows a left
• 10:12hepatectomy, which means,
• 10:14segments two, three, and four
• 10:16are resected. So the left
• 10:17portion of liver is, resected.
• 10:18The right portion remains.
• 10:21Picture c shows an extended
• 10:23right hepatectomy, which means we
• 10:24take out the entire right
• 10:25liver and part of the,
• 10:27left liver as well.
• 10:29And then segment,
• 10:30picture D shows
• 10:33a left lateral
• 10:35sectionectomy,
• 10:36which means we take out
• 10:37part of the left lateral
• 10:38liver, segments two and three.
• 10:40And then picture e
• 10:42shows, an extended left hepatectomy.
• 10:45One thing I do wanna
• 10:46comment on is, you know,
• 10:47this is a lot of
• 10:48liver that we resect, and
• 10:49this is, you know, the
• 10:50resilience of the human body
• 10:51because,
• 10:52you know, when we were
• 10:53we can resect
• 10:54up to eighty percent of
• 10:56one's liver,
• 10:57with some anatomical considerations,
• 11:00in play,
• 11:02and the liver will regenerate
• 11:03for individuals and people patients
• 11:05can go on to live
• 11:06a very,
• 11:07solid quality of life in
• 11:08the long term
• 11:10even with,
• 11:11major operations such as, such
• 11:13as the ones that are
• 11:14listed over here.
• 11:18Synchronous hepatic metastases, I alluded
• 11:20to a bit earlier, and
• 11:21these are metastases that are,
• 11:23essentially diagnosed at at the
• 11:25time that the colon cancer
• 11:26is diagnosed, and it's found
• 11:28in about twenty to thirty
• 11:30four percent of individuals with
• 11:31the new colorectal cancer diagnosis.
• 11:33And I had mentioned before
• 11:35that metastasis development of metastasis
• 11:37more than six months after
• 11:38the primary tumor.
• 11:40For patients with synchronous hepatic
• 11:42metastases, there are different ways
• 11:44to approach it. And, at
• 11:45Yale, we have a great
• 11:46multidisciplinary team that does that
• 11:48includes our intervention radiologists, our
• 11:50radiation oncologist, our medical oncologist,
• 11:53and other surgeons other in
• 11:54addition to HPV surgical oncologist
• 11:56such as colorectal surgeons. One
• 11:58thing that comes up frequently
• 11:59is in patients that present
• 12:01with a synchronous pattern.
• 12:03Sometimes we can remove the
• 12:04colon tumor first,
• 12:06and there's some,
• 12:07advantages and disadvantages to doing
• 12:09in that in that sort
• 12:09of a manner. So that's
• 12:11what's called the primary first
• 12:12approach.
• 12:13Another is a combined approach,
• 12:15and this is where the
• 12:15primary tumor where the colon
• 12:17tumor arose from and the,
• 12:19liver metastases are resected in
• 12:21one, separate in one single
• 12:23setting.
• 12:24This, it can be applied
• 12:26to many patients,
• 12:28but it tends to work
• 12:29well if you're we're not
• 12:30doing a major liver resection
• 12:31and, we're not doing a
• 12:33major, colorectal resection at the
• 12:35same time.
• 12:36So but sometimes we can
• 12:38remove both tumors at the
• 12:39same time. And then there's
• 12:41a metastasis
• 12:42first approach, and this is
• 12:43something that I tend to
• 12:44favor,
• 12:46if a combined approach is
• 12:47not possible
• 12:48because, a hepatectomy
• 12:50that meaning the hepatic metastasis
• 12:52is removed first,
• 12:54and there's some advantages to
• 12:55this sort of approach as
• 12:56well too.
• 12:57But all of these approaches
• 12:58are are,
• 12:59are well accepted.
• 13:03Sometimes if patients present with
• 13:05bilateral metastases, which means there
• 13:06are metastases present in the
• 13:08right liver and the left
• 13:09liver,
• 13:11it could create some challenges.
• 13:13However, I do want to
• 13:15say that we, even in
• 13:16the presence of bilateral hepatic
• 13:18metastases,
• 13:19is not what's called a
• 13:20contraindication of surgery. There are
• 13:22patients that present with bilateral
• 13:24hepatic metastases where we can
• 13:25resect both,
• 13:28sides of metastases.
• 13:30And, and this is something
• 13:31that we consider, and we
• 13:33do treat patients like this
• 13:37relatively extensively here at our
• 13:39Yale Cancer Center. So it's
• 13:40a it's a very good
• 13:41armamentarium to have. So bilateral
• 13:43metastases,
• 13:45patient patient with bilateral hepatic
• 13:46metastases can still undergo,
• 13:48surgical approach.
• 13:50And this is just these
• 13:51are some examples of how,
• 13:53we sometimes consider patients, that
• 13:55present bilateral metastases.
• 13:57Some patients will consider giving
• 13:59them systemic therapy upfront with
• 14:01doctor Kortmansky and his medical
• 14:02oncology colleagues and then consider
• 14:04doing,
• 14:05removing a part part of
• 14:06the liver or recall what's
• 14:07called a minor hepatectomy.
• 14:09And in that kind of
• 14:10a circumstance, sometimes,
• 14:12the you know, I think
• 14:13doctor Madoff may talk about
• 14:15it, but, sometimes the liver
• 14:16needs to have what's called
• 14:18hypertrophy
• 14:19in order to recover from
• 14:20two liver operation.
• 14:22That's where we'll involve doctor
• 14:23Madoff's team to do what's
• 14:24called a portal vein embolization
• 14:26and then take remove do
• 14:28the major hepatectomy in a
• 14:29second setting and then finish
• 14:31the systemic therapy. So that
• 14:32is one approach that we
• 14:33sometimes use. Another approach, can
• 14:36be doing a minor hepatectomy
• 14:37first,
• 14:38plus or minus the PBE,
• 14:39then doing a major hepatectomy,
• 14:42later and then, saving systemic
• 14:44therapy for later.
• 14:45So that's another approach.
• 14:47And then sometimes a single
• 14:48liver surgery is possible even
• 14:50in the case of bilateral
• 14:51hepatic metastases, and this is
• 14:52where parenchymal sparing resections,
• 14:55can become a bit more
• 14:56useful.
• 14:57There's a concept known as
• 14:59disappearing liver metastases. And the
• 15:00reason I wanna mention this
• 15:01is because,
• 15:03I think it's important that,
• 15:05when a patient is diagnosed
• 15:06with colon cancer and liver
• 15:08metastases, they see the hepatobiliary
• 15:10surgeon early on in the
• 15:11diagnosis
• 15:12because sometimes
• 15:13patients can be given systemic
• 15:15therapy and the lesions will
• 15:17disappear.
• 15:18And, and that can create
• 15:20some challenges down the road.
• 15:21So that's why we love
• 15:22for our patients to, see
• 15:24our multidisciplinary
• 15:25team,
• 15:26early on,
• 15:28all the disciplines in order
• 15:29to help provide the best
• 15:31not just short outcome, best
• 15:32long term outcome.
• 15:36Ablation, I'll go through this
• 15:38relatively quickly because I believe
• 15:39Doctor. Madoff will talk about
• 15:40it, but this is a
• 15:41very good option that we
• 15:42sometimes use as a surgical
• 15:44oncologist where we burn the
• 15:46tumor with microwave ablation and
• 15:48less frequently radio frequency ablation
• 15:50these days.
• 15:52And there is data to
• 15:53support the use of, ablation
• 15:55for the treatment for patients.
• 15:58And there is a more
• 15:59recent trial called the collision
• 16:01trial where microwave treatment,
• 16:03can be effective in tumors
• 16:04less than three centimeters.
• 16:06However,
• 16:07and so that's that's a
• 16:09very important study that was
• 16:10published relatively recently.
• 16:12And the way I look
• 16:13at that study is it
• 16:13can it shows that microwave
• 16:15ablation can be very good
• 16:16adjunct,
• 16:17to treating patients with colorectal
• 16:19liver metastases, and sometimes it
• 16:20can be used patients with
• 16:21bilobar hepatic metastases.
• 16:24But I do want to
• 16:25say that still, if a
• 16:26resection is possible,
• 16:28it tends to be better
• 16:29oncologically, and I think in
• 16:31future years, we may hear
• 16:32a little bit more about
• 16:33that.
• 16:36And the the last bit
• 16:37of the talk is to
• 16:38talk about, I'll talk about
• 16:40HAI pumps, which, will be
• 16:42talked a bit more later.
• 16:43And the concept behind this
• 16:45is many patients that do
• 16:47undergo liver resection,
• 16:50can develop a liver,
• 16:52recurrence.
• 16:53And, that's a relatively this
• 16:55is that's not an uncommon
• 16:56scenario that we're faced with.
• 16:59And the reason for that
• 17:00is, the biology of colorectal
• 17:02cancer,
• 17:03is unique and compared to
• 17:05many other cancers where patients
• 17:06can develop liver only metastases,
• 17:09and HAI therapy is a
• 17:11form of chemotherapy to provide
• 17:13liver specific chemotherapy
• 17:15where our surgical oncology team,
• 17:17we have an HAI program,
• 17:19inserts a catheter into gas
• 17:21an artery that eventually supplies
• 17:23blood to the liver, and
• 17:24chemotherapy can be administered.
• 17:26I'll go through this relatively
• 17:28quickly as I know doctor
• 17:29Corvansky talked about it.
• 17:32And but the principle is
• 17:33that the liver metastases are
• 17:35perfused
• 17:36by the hepatic artery. So
• 17:37if one can give chemotherapy,
• 17:39through that hepatic artery,
• 17:41you can provide a much
• 17:42higher dose of chemotherapy,
• 17:44than can be administered just
• 17:46through intravenous
• 17:47fashion,
• 17:48and it can have a
• 17:49very good effect,
• 17:51of cytotoxicity
• 17:52to the liver metastasis tumors.
• 17:56I will skip this slide,
• 17:57but I think doctor Korvansky
• 17:58may talk about this, but
• 17:59there is good evidence,
• 18:01that HAI therapy provides oncologic
• 18:04benefit.
• 18:06Generally speaking, these are patients
• 18:07we will consider for HAI
• 18:09therapy.
• 18:10One has to be histological
• 18:12confirmation of colorectal liver metastasis.
• 18:14We also do,
• 18:16consider HAI therapy for patients
• 18:18with intrepatic cholangiocarcinoma,
• 18:19which we're not going to
• 18:20talk about today. Patients must
• 18:22be fit to undergo a
• 18:23major abdominal operation, and it
• 18:25is not a minor operation,
• 18:27but it's not a major
• 18:28operation either.
• 18:30They cannot have evidence of
• 18:31portal hypertension or portal vein
• 18:33thrombosis.
• 18:34They have to have good
• 18:35liver parameters.
• 18:37The favorable hepatic anatomy, you
• 18:38know, that's a little bit
• 18:39subjective because there's a lot
• 18:41of innovative ways where the
• 18:42anatomy can be worked around
• 18:45and limited to, you know,
• 18:47no extrahepatic disease,
• 18:49generally speaking.
• 18:52This is one algorithm that
• 18:53we sometimes use,
• 18:55where patients present with resectable
• 18:57colorectal liver metastases. They had
• 18:59no extra hepatic disease.
• 19:00If they are at high
• 19:01risk for liver only recurrence,
• 19:03we can consider placing one
• 19:05of these liver pumps at
• 19:06the time that the liver
• 19:07resection is performed.
• 19:09But the more common scenario
• 19:10is patients present with unresectable
• 19:12colon cancer liver metastasis.
• 19:14They'll get systemic chemotherapy,
• 19:16by our medical oncology team,
• 19:18and there's no development or
• 19:20progression of disease.
• 19:22And,
• 19:23and sometimes with the or
• 19:25there is development progression of
• 19:27the extra of, extrahepatic disease.
• 19:29In that case, we'll we're
• 19:30less likely considered HAI.
• 19:32But sometimes there's a limited
• 19:34or no response, and we
• 19:35can consider HAI in these
• 19:37kinds of circumstances where the
• 19:38pump is placed.
• 19:42This is a cartoon depicting
• 19:44what exactly we do. So
• 19:46the pump is,
• 19:47is about the size of
• 19:48a hockey puck that's placed
• 19:50in the abdominal wall, underneath
• 19:52the skin,
• 19:54and oftentimes, we'll put on
• 19:55the left side of the
• 19:56patient, but there's other areas
• 19:57we can place these pumps,
• 19:59pumps as well too.
• 20:00The pump is connected to
• 20:02a catheter,
• 20:03which is placed in this
• 20:04hepatic,
• 20:05gastroduodenal
• 20:06artery, which supplies
• 20:07which, connects to the hepatic
• 20:09artery, which is where this,
• 20:11chemotherapy is is, is delivered.
• 20:14Actually, after the implant, it's
• 20:15interesting that the body heat
• 20:17serves as an ongoing power
• 20:18supply for the drug delivery,
• 20:21and, our medical oncology,
• 20:23HAI team,
• 20:25helps manage this very carefully
• 20:26and very well.
• 20:28Everyone that, we consider for
• 20:30an HAI pump at EL
• 20:32is part of our HAI
• 20:33pump program,
• 20:34which is part of a
• 20:35multidisciplinary
• 20:36team.
• 20:37Patients are presented at our
• 20:39multidisciplinary
• 20:40tumor board.
• 20:41They are consulted. They seek
• 20:42different consultants such as surgical
• 20:44oncologists, medical oncologists,
• 20:46a social worker. They work
• 20:48with their radiologists,
• 20:50to get a good mapping
• 20:51study. The catheter is placed.
• 20:53Our nuclear medicine,
• 20:54doctors,
• 20:56help confirm that the catheter
• 20:57is in the right spot,
• 20:58and then the medical oncology
• 20:59team takes over.
• 21:01So this is,
• 21:03one of the last slides,
• 21:04but this is a proposed
• 21:05algorithm for the management of
• 21:07hepatic metastases.
• 21:09Again, it's important to have
• 21:10the the patient seen by
• 21:12HPB surgical oncologist early on.
• 21:14If one has a resectable
• 21:16disease,
• 21:17sometimes they can get systemic
• 21:19therapy for four to six
• 21:20cycles early on and then
• 21:21undergo a liver resection.
• 21:23Or sometimes they can undergo
• 21:24liver surgery upfront, and we
• 21:26talked a little bit more
• 21:27about we talked a little
• 21:28bit about the different kinds
• 21:29of surgical approaches
• 21:30and sometimes post op post,
• 21:32liver surgery,
• 21:33the post hepatectomy therapy,
• 21:36systemic therapies needed. There are
• 21:38some patients that may present
• 21:39with unresectable disease,
• 21:41where we, start treatment with
• 21:42systemic therapy. We they'll be
• 21:45reimaged, and then at that
• 21:46point, we can consider liver
• 21:48surgery for those that have
• 21:49treatment response or consider additional
• 21:51systemic therapy or even liver
• 21:53directed therapy as was mentioned
• 21:54as well.
• 21:56So So in summary for
• 21:57colorectal cancer liver metastases,
• 21:59about fifty percent of patients
• 22:00with colon cancer liver with
• 22:02colorectal cancer will develop,
• 22:05or present with liver metastases.
• 22:07Liver surgery is an important
• 22:08armamentarium
• 22:09for patients with colorectal cancer
• 22:11liver metastases.
• 22:12We went over hepatectomies,
• 22:14microwave ablations,
• 22:15hepatic articular infusion pump placement.
• 22:18Multidisciplinary
• 22:19care incorporating liver surgery can
• 22:21improve patient survival,
• 22:24and that is in the
• 22:25case of synchronous and metacritic
• 22:26metastasis,
• 22:28disappearing lesions, and bilateral hepatic
• 22:30metastases.
• 22:32Thank you for your time.
• 22:34I'm gonna hand it off
• 22:35to my colleagues, for the
• 22:36next part of the talk.
• 22:39Alright. Thank you, doctor Khan.
• 22:40That was a fantastic talk.
• 22:43Just to help us stay
• 22:44on time, I'm gonna request,
• 22:47that,
• 22:48question. We'll address the questions,
• 22:51at the end of all
• 22:52of the talks,
• 22:53but certainly along the way,
• 22:55feel free to enter them
• 22:56into the,
• 22:58the chat.
• 22:59The panelists do have the
• 23:01option to respond,
• 23:04in the chat as well,
• 23:06if they feel so so
• 23:08compelled.
• 23:10On switching gears, I'm gonna
• 23:12talk,
• 23:13about,
• 23:15the chemotherapy.
• 23:18And I wanted to focus
• 23:22my part of this talk,
• 23:25not on all of chemotherapy
• 23:27for,
• 23:28metastatic colorectal,
• 23:30cancer, which could take a
• 23:31few hours,
• 23:33but really focusing
• 23:35on a follow-up to doctor
• 23:37Khan's talk in terms of
• 23:39the role of perioperative
• 23:40chemotherapy,
• 23:42in patients who are undergoing
• 23:44resection,
• 23:46and then,
• 23:47the role
• 23:48of hepatic arterial infusion
• 23:50therapy, both for patients who
• 23:51have had resection
• 23:53as well as patients who
• 23:54are unresectable.
• 23:56I will emphasize that for
• 23:58patients who are upfront
• 24:00unresectable,
• 24:02or who have extra hepatic
• 24:04disease,
• 24:06it's always important for us
• 24:08to put our best foot
• 24:09forward in terms of our
• 24:10chemotherapy choices based on,
• 24:13the tumor sightedness and and
• 24:15tumor biology
• 24:17and,
• 24:17molecular profiling.
• 24:20I I think there are
• 24:21three important studies,
• 24:23to discuss,
• 24:25in the world of perioperative
• 24:27chemotherapy,
• 24:29EORTC
• 24:30four zero nine eight three
• 24:32or the EPOC study,
• 24:36which was a European study,
• 24:38JCOG zero six zero three,
• 24:41which was a Japanese study
• 24:43that just, reported out its
• 24:45long term,
• 24:47data,
• 24:48in January, and
• 24:50then new epoch,
• 24:53which was a follow-up to
• 24:54the original EORTC
• 24:57study.
• 25:03The reason why I chose
• 25:04these, three studies was that
• 25:07there has been a lot
• 25:08of work
• 25:09that was done,
• 25:11prior to those studies.
• 25:14Looking at,
• 25:16chemotherapy
• 25:17and surgery,
• 25:18some studies used,
• 25:20hepatic arterial infusion.
• 25:23The flaw in all of
• 25:24these studies is that they
• 25:25tended to be poorly powered,
• 25:28to answer the question
• 25:30or had incomplete
• 25:32accrual.
• 25:34But
• 25:34if you look at the
• 25:35general trend of that data,
• 25:37we do see that there
• 25:38is improvements in progression free
• 25:40survival,
• 25:42but not improvements in median
• 25:44overall survival.
• 25:47And so EORTC
• 25:49four zero nine eight three
• 25:50looked at perioperative
• 25:52chemotherapy
• 25:53with FOLFOX
• 25:54four, a
• 25:55modern regimen incorporating oxaliplatin,
• 25:58whereas prior studies used five
• 26:00f u alone,
• 26:01and surgery versus surgery alone
• 26:04in patients who had
• 26:06resectable liver metastases.
• 26:08This study
• 26:10enrolled three hundred and sixty
• 26:11four patients with up to
• 26:13four liver metastases.
• 26:15All patients had previously had
• 26:17their primary tumor resected.
• 26:20Patients received either surgery alone
• 26:22or six cycles of FOLFOX,
• 26:26before,
• 26:27surgery and then an additional
• 26:28six after.
• 26:30The primary endpoint was progression
• 26:32free survival.
• 26:34A hundred and eighty two
• 26:35patients were enrolled to each
• 26:37arm.
• 26:38A hundred and seventy one
• 26:40in each arm turned out
• 26:41to be
• 26:42eligible. Patients were evenly matched
• 26:45for stage, number of liver
• 26:47metastases,
• 26:48the disease free interval between
• 26:50their primary tumor,
• 26:52and, metastatic disease,
• 26:55prior treatments,
• 26:56and CEA.
• 26:58In the group that got
• 26:59perioperative
• 27:00chemotherapy,
• 27:02eighty or eighty percent completed
• 27:04their preoperative treatment,
• 27:06with ninety two percent dose
• 27:07intensity
• 27:09and a response rate of
• 27:10forty three percent,
• 27:12with three percent CR,
• 27:14a number that corresponds with
• 27:16what we usually see with
• 27:18FOLFOX chemotherapy,
• 27:20and seven percent progressed
• 27:22on their,
• 27:23preoperative treatment.
• 27:25Ultimately, of the hundred and
• 27:27seventy one who are eligible,
• 27:28a hundred and fifty nine
• 27:30went on to surgery,
• 27:32but only forty six percent
• 27:33were able to complete their
• 27:35postoperative
• 27:36chemotherapy.
• 27:37For the surgery alone group,
• 27:39a hundred and seventy out
• 27:40of the one seventy one,
• 27:42went on to surgery.
• 27:46And so the the progression
• 27:48free survival was the first
• 27:50data that was presented.
• 27:52They broke it up into,
• 27:55multiple
• 27:56subsets looking at all those
• 27:58who were,
• 27:59who were randomly assigned, patients
• 28:02who were eligible, and then,
• 28:03ultimately, the patients who underwent
• 28:05resection.
• 28:06But it's a consistent theme,
• 28:09which is that, the three
• 28:11year progression free survival
• 28:14increased by about seven and
• 28:15a half percent
• 28:17from twenty eight point one
• 28:18percent to thirty five point
• 28:20four percent,
• 28:22and median progression free survival
• 28:24improved from eleven point seven
• 28:26to eighteen point seven months.
• 28:29And so this,
• 28:31PFS data was,
• 28:34was presented initially, and perioperative
• 28:37chemotherapy
• 28:38based on this study,
• 28:40really became a standard approach.
• 28:44What they saw in this
• 28:45study is that the predictors
• 28:47of benefit from perioperative chemotherapy
• 28:50included
• 28:51patients who had a CEA
• 28:52level greater than five,
• 28:55a good performance status,
• 28:57BMI less than thirty.
• 28:59But, interestingly, the number of
• 29:01liver metastases,
• 29:02whether it was one or
• 29:03four,
• 29:04did not predict the chemotherapy
• 29:06benefit.
• 29:09But, alas, when they published
• 29:11the long term results in
• 29:13twenty thirteen,
• 29:15that disease that improvement in
• 29:17disease free survival
• 29:18did not translate into an
• 29:20overall survival advantage,
• 29:23presumed to be related to
• 29:25the secondary
• 29:26therapies that these patients,
• 29:28received.
• 29:32One of the questions that
• 29:33comes up,
• 29:34when we think about,
• 29:36giving preoperative chemotherapy
• 29:38is whether that enhances surgical
• 29:40morbidity.
• 29:42The risk of surgical complications
• 29:44does increase
• 29:46with the number of cycles
• 29:47of chemotherapy that patients receive.
• 29:50But if it is,
• 29:52below
• 29:52six or below, it tends
• 29:54to be,
• 29:56safe, which is,
• 29:58why our surgical colleagues often
• 30:00ask us
• 30:01to limit any,
• 30:03preoperative chemotherapy
• 30:05to that three month range.
• 30:10Just this past January,
• 30:13j cog zero six zero
• 30:15three,
• 30:17presented their long term follow-up
• 30:19of this randomized,
• 30:21trial comparing hepatectomy
• 30:24followed by FOLFOX six with
• 30:26hepatectomy
• 30:27alone.
• 30:28This study was designed a
• 30:30little bit differently in that,
• 30:32all patients had upfront hepatectomy,
• 30:35and then the investigational
• 30:37group received their chemotherapy
• 30:39after surgery.
• 30:42The primary endpoint was disease
• 30:44free survival
• 30:46with a planned secondary endpoint
• 30:48of overall survival.
• 30:50It enrolled three hundred patients
• 30:52in a one to one
• 30:53fashion.
• 30:54To be eligible, the patients
• 30:56had to have their primary
• 30:57tumor removed and could not
• 30:59have received prior oxaliplatin.
• 31:03But it is a similar
• 31:05theme to what we saw
• 31:06in EORTC
• 31:08study
• 31:09In the upper,
• 31:12tables, we see that, the
• 31:14overall survival was no different
• 31:16in those patients who received
• 31:19postoperative
• 31:19chemotherapy
• 31:21even though,
• 31:22disease free survival
• 31:25was in fact improved with
• 31:26the use of perioperative
• 31:28chemotherapy.
• 31:28So results that really
• 31:30corroborate,
• 31:32what we saw,
• 31:33from the European cohort.
• 31:39Lastly,
• 31:40I wanted to talk about,
• 31:42new epoch,
• 31:44which was
• 31:46because the original epoch study
• 31:48showed those benefits in disease
• 31:50free survival. This study was
• 31:52then designed,
• 31:54where all patients were received
• 31:56perioperative
• 31:57Fofox.
• 31:59Two hundred and fifty seven
• 32:00KRAS wild type patients were
• 32:02then
• 32:03randomized to receive Fofox
• 32:06with or without,
• 32:08cetuximab.
• 32:12And this study showed
• 32:13surprising results. It showed that
• 32:15the median overall survival
• 32:18was actually better in the
• 32:20group that did not get
• 32:21cetuximab,
• 32:22eighty one months versus fifty
• 32:24five point four months.
• 32:27As we know, in the
• 32:28metastatic setting, the addition of,
• 32:32cetuximab or, anti EGFR therapy
• 32:35in patients with metastatic disease
• 32:37has been shown to improve
• 32:39survival,
• 32:40but we do not see
• 32:41that in,
• 32:43in this resected population. We
• 32:45did not see,
• 32:47a benefit in progression free
• 32:49survival as we had in
• 32:50the other studies.
• 32:52So this certainly gives us
• 32:54some pause
• 32:55about using,
• 32:57cetuximab
• 32:58in patients that we,
• 33:00think going into their treatment
• 33:03already have resectable disease.
• 33:09Trying to explain this unexpected,
• 33:11result is has been challenging.
• 33:14There are small differences
• 33:16in the resection rates,
• 33:18between the two groups.
• 33:20There was similar toxicity.
• 33:23In the group that received
• 33:24cetuximab,
• 33:25there was a higher number
• 33:27who had presented with synchronous
• 33:28METs and a higher number
• 33:30that had presented with large
• 33:31metastases,
• 33:33both of which are risk
• 33:34factors for relapse
• 33:36of, metastatic
• 33:37disease.
• 33:39And
• 33:40a higher number, although relatively
• 33:42small, had,
• 33:43extra hepatic disease.
• 33:46But the
• 33:47when they did a
• 33:49analysis,
• 33:50they saw that the detriment
• 33:52was actually in the favorable
• 33:54risk groups and not in
• 33:55these higher risk groups.
• 34:00And so if
• 34:02chemotherapy
• 34:03alone,
• 34:05has not shown to improve
• 34:07overall survival,
• 34:09although I would argue that
• 34:10improvements in disease free survival
• 34:12is in fact a meaningful
• 34:13benefit.
• 34:15But if the chemotherapy
• 34:17hasn't improved overall survival,
• 34:20it raises the question of
• 34:21what else can we do
• 34:22that might improve those opportunities.
• 34:26And so that's where,
• 34:28the role of hepatic arterial
• 34:29infusion,
• 34:31really has its applications in
• 34:33in these this group of
• 34:35patients.
• 34:36For patients that have unresectable
• 34:38disease,
• 34:39it can,
• 34:41reduce tumor burden
• 34:42and
• 34:43and potentially convert patients to
• 34:45a receptacle disease,
• 34:48and it could actually improve
• 34:50survival even independent of that
• 34:52receptibility.
• 34:54In the adjuvant setting, it
• 34:55can,
• 34:57it may reduce the likelihood
• 34:58of recurrence post resection,
• 35:02and it has shown,
• 35:03improvements in two year survival
• 35:06in a randomized trial.
• 35:09Admittedly, that study is an
• 35:11old study, and additional work
• 35:13needs to be done.
• 35:16As doctor Khan already,
• 35:19reviewed,
• 35:21the the general premise of
• 35:23hepatic arterial infusion therapy is
• 35:25that,
• 35:26very high doses of floxiridine,
• 35:29which is the active metabolite
• 35:31of five f u,
• 35:33can be infused into the
• 35:34liver
• 35:37at concentrations
• 35:38that are four hundred times
• 35:39that
• 35:40of intravenous infusion,
• 35:43but because it gets metabolized
• 35:45so quickly,
• 35:46we don't see,
• 35:48the systemic toxicity.
• 35:53In the adjuvant setting,
• 35:55this was a study from
• 35:57nineteen ninety nine.
• 36:00It is now twenty seven
• 36:01years later, and this is
• 36:02still the best study that
• 36:05we have
• 36:06that showed in a hundred
• 36:07and fifty six patients,
• 36:10chemo overall survival was improved
• 36:13in patients who had surgery
• 36:15followed by
• 36:17HAI with systemic five f
• 36:19u alone
• 36:21versus five f u alone,
• 36:23and that this study improved,
• 36:28specifically liver,
• 36:30recurrence.
• 36:34Patients who,
• 36:36could might still develop extra
• 36:38hepatic disease, which was often
• 36:40a cause of mortality in
• 36:41this group.
• 36:47And looking at that to
• 36:49how this translated
• 36:51to
• 36:52potential cure,
• 36:55there was,
• 36:56the group from the Netherlands
• 36:59that reported out their single
• 37:01center experience,
• 37:04of,
• 37:05twenty three,
• 37:07over twenty three hundred patients,
• 37:10who got systemic chemo plus
• 37:12HAI
• 37:13versus systemic chemotherapy
• 37:15alone,
• 37:16and showed a marked improvement
• 37:19in the ten year survival
• 37:20rate from twenty three,
• 37:23to thirty eight percent.
• 37:26And this was both with
• 37:27five f u alone as
• 37:29their dataset went all the
• 37:30way back to nineteen ninety
• 37:31two as well as with
• 37:33the addition of arino t
• 37:34can and,
• 37:36oxaliplatin.
• 37:37And so,
• 37:39there remains interest in this
• 37:41approach,
• 37:42to help,
• 37:42reduce the risk of,
• 37:45recurrence and improve survival in
• 37:47this population.
• 37:51Many patients are not resectable
• 37:53at the time of,
• 37:57of their presentation with metastatic
• 37:59disease.
• 38:00We certainly have a number
• 38:02of chemotherapy,
• 38:04choices in the in those
• 38:06patients,
• 38:08especially if,
• 38:12we understand their molecular
• 38:14profile.
• 38:15But we have seen with
• 38:17the addition of,
• 38:19hepatic arterial infusion
• 38:21to,
• 38:22chemotherapy,
• 38:25that we can,
• 38:26induce a response rate of
• 38:28seventy three percent,
• 38:30up to eighty six percent
• 38:32if this is patient's first
• 38:33line of treatment,
• 38:35less if they've been previously
• 38:36treated.
• 38:38And about half of those
• 38:39patients,
• 38:40in this dataset,
• 38:42were converted
• 38:43to resection.
• 38:46Looking at the curve on
• 38:47the right, you can see
• 38:48that those who underwent resection,
• 38:51have a better survival than
• 38:52those,
• 38:53who don't.
• 38:57These,
• 38:58improvements,
• 39:01in survival
• 39:02have been seen,
• 39:04even in patients that don't
• 39:05go on to have,
• 39:07surgical resection.
• 39:10Looking at both,
• 39:13the pump plus modern chemotherapy
• 39:15regimens,
• 39:16which includes oxaliplatin
• 39:18or arinotecan,
• 39:21with or without biologics. Although
• 39:23I will say for safety
• 39:24reasons, we don't combine
• 39:26bevacizumab,
• 39:28with hepatic arterial infusion therapy,
• 39:32because of the marked increase
• 39:33in,
• 39:35biliary sclerosis in these patients.
• 39:42And then,
• 39:44lastly, I just wanna present
• 39:45this group. So this is
• 39:47a,
• 39:49experience from Memorial of patients
• 39:51who were where
• 39:53systemic therapy
• 39:55and hepatic arterial infusion therapy
• 39:57was their first line of
• 39:58treatment. They presented with unresectable
• 40:01disease.
• 40:02And in this group, the
• 40:04conversion to resection rate,
• 40:07was sixty percent. And so
• 40:09this is, again, a small
• 40:10cohort,
• 40:12but does show,
• 40:14the potential to,
• 40:16convert,
• 40:17these,
• 40:18these patients to resection.
• 40:23And so it is a
• 40:24a reasonable consideration.
• 40:28For patients that have
• 40:30KRAS
• 40:31wild type disease,
• 40:34we have seen high conversion
• 40:36rates with modern chemotherapy
• 40:38regimens like FOLFOXURY
• 40:42as well. And so,
• 40:45one of the
• 40:46important
• 40:47points when I talk about
• 40:49this type of treatment,
• 40:52is that,
• 40:54there is still more knowledge
• 40:55that is needed.
• 40:58At Yale, we are part
• 41:00of the, a HAI consortium,
• 41:04which, represents
• 41:08multiple institutions.
• 41:09I think,
• 41:11over,
• 41:12sixty institutions
• 41:14around the country,
• 41:16that are really trying to
• 41:18take a more collaborative and
• 41:20prospective approach to this
• 41:22data,
• 41:24so that we are not
• 41:25left with,
• 41:26only single center experiences
• 41:28as we move forward.
• 41:33And so in summary, for
• 41:35HAI,
• 41:36for unresectable
• 41:37disease, it can contribute to,
• 41:41conversion there,
• 41:43of patients to resection,
• 41:47and improve overall survival in
• 41:48patient or median overall survival
• 41:50in patients who are not
• 41:51resectable,
• 41:53in the adjuvant setting,
• 41:55it can,
• 41:56potentially improve,
• 41:58both two year and ten
• 41:59year survival as well.
• 42:04And so in summary for
• 42:06this part,
• 42:07perioperative
• 42:09chemotherapy
• 42:10the role of perioperative chemotherapy
• 42:12remains unclear. Disease free survival
• 42:14is improved,
• 42:15but there's no impact on
• 42:17overall survival.
• 42:19HAI can potentially improve overall
• 42:22survival in some patients,
• 42:24but there remains more work
• 42:26to be done.
• 42:29And with that, I am
• 42:30going to pass the baton,
• 42:33to doctor Madoff who will,
• 42:35talk to us about,
• 42:37the role of interventional radiology
• 42:39in treating these this group
• 42:40of patients.
• 42:50Can you hear me?
• 42:56Thanks, Jeremy. You you you
• 42:57can hear me?
• 43:00Yes. We can.
• 43:04Okay. So I guess, we'll
• 43:06get started.
• 43:07I'd like to thank, Jeremy
• 43:09and, my colleagues here for
• 43:10inviting me to discuss the
• 43:12role of interventional oncology,
• 43:14in the setting of colorectal
• 43:15liver metastases.
• 43:17These are just, my disclosures.
• 43:20So we've already heard a
• 43:21lot
• 43:22about,
• 43:23the global burden of colorectal
• 43:25cancer and, and liver metastases.
• 43:28Not to get it to
• 43:29keep repeating ourselves, but, we
• 43:31all know that about fifty
• 43:32percent of colorectal cancer patients
• 43:34develop metastases during the course
• 43:36of their disease,
• 43:37and,
• 43:38liver metastases
• 43:40represents the major cause of,
• 43:43colorectal
• 43:44cancer
• 43:45mortality.
• 43:46We also heard that hepatic
• 43:48resection offers the best chance
• 43:49of cure, but most patients,
• 43:51when they present are not
• 43:53receptible at the time of
• 43:54diagnosis.
• 43:55One thing I did wanna
• 43:56point out is that I
• 43:57did attend the colorectal liver
• 43:58metastases consensus conference down at
• 44:00MD Anderson a few weeks
• 44:01ago, and I can tell
• 44:02you that there is a
• 44:04lot of controversy.
• 44:05And whatever we discuss, tonight,
• 44:08there is, data to support,
• 44:10but there's also data to
• 44:11support other strategies
• 44:13as well.
• 44:14So what is interventional oncology?
• 44:16I mean, it's clearly different
• 44:17than radiation oncology, which, doctor
• 44:19Du will talk about. But,
• 44:21radiation oncology is a subspecialty
• 44:23of,
• 44:24interventional radiology
• 44:26that utilizes minimally invasive image
• 44:28guided procedures to diagnose and
• 44:30treat patients with various forms
• 44:32of cancer. I would say
• 44:33that most of you would
• 44:34know us from, doing your
• 44:36ports
• 44:37and doing your biopsies,
• 44:39but, there's definitely a lot
• 44:40more to interventional oncology than
• 44:42that.
• 44:44As we'll discuss,
• 44:45the benefits of, primary interventional
• 44:48oncology treatment
• 44:49include immediate tumor recital, effects.
• 44:53They are minimally invasive,
• 44:55and, they're also, have minimal
• 44:57systemic side effects, so ultimately
• 44:59can improve
• 45:00the quality of life. We're
• 45:02at this time making the
• 45:03case of becoming the fourth
• 45:04pillar of cancer care. Interventional
• 45:06oncologists,
• 45:08are, you know, very participate
• 45:10heavily in, tumor boards. We're
• 45:12part of multiple NCCN guidelines.
• 45:14I'm actually on the kidney
• 45:15cancer one for, the Yale
• 45:16as their Yale representative.
• 45:18And there are a number
• 45:19of clinical trials assessing the
• 45:20role of percutaneous
• 45:21management,
• 45:22and there are a number
• 45:23of trials here. And some
• 45:24of them, we will discuss,
• 45:26during this talk.
• 45:29What I wanted to focus
• 45:30on first is the core
• 45:31IO strategies.
• 45:33The goal is to enable
• 45:34curative therapy
• 45:36or improve local disease control.
• 45:38And as you've already heard,
• 45:40we have options such as
• 45:41tumor ablation,
• 45:42we have transarterial
• 45:44therapy,
• 45:45and we also have preoperative
• 45:46liver augmentation,
• 45:48which, doctor Khan has, briefly
• 45:50alluded to. Now a number
• 45:51of these,
• 45:53treatments will depend on tumor
• 45:56histology,
• 45:57the number of location the
• 45:58number and location of tumors
• 46:00within the liver,
• 46:01the extent of the patient's
• 46:03underlying liver disease,
• 46:05and the presence or absence
• 46:07of extrahepatic
• 46:08disease.
• 46:09Now the first strategy we'll
• 46:10discuss is tumor ablation.
• 46:12This is used to percutaneously
• 46:14eradicate all viable malignant cells
• 46:16and spare normal surrounding tissues.
• 46:19And we also treat tumors
• 46:21that have, that are,
• 46:22have unfavorable locations or patterns
• 46:25of distribution
• 46:26for resection and or whether
• 46:28patients have multiple comorbidities.
• 46:32Most often, these are used
• 46:33in patients what we would
• 46:34have considered low volume disease
• 46:36and debulking,
• 46:38and, typically, these are outpatient
• 46:40procedures and repeatable.
• 46:42Now there's a lot of
• 46:43different options.
• 46:44I would say that a
• 46:45lot of them have similar
• 46:46outcomes, whether it be radiofrequency
• 46:48ablation, microwave ablation,
• 46:51cryoablation.
• 46:52There's another, entity called irreversible
• 46:55electroporation, which kills cells,
• 46:57by, changing the electron maybe,
• 47:01ionic potentials across cell membranes.
• 47:03And there's actually a new
• 47:04one called radiation segmentectomy
• 47:06where you can deliver high
• 47:07dose of radiation
• 47:08transcatheter
• 47:09into a segment and kill
• 47:10tumors in that regard.
• 47:13You've already heard a little
• 47:14bit about transarterial therapy. This
• 47:16was initiated about fifty years
• 47:17ago, mostly in the studying
• 47:19early in the studying of,
• 47:20HCC.
• 47:22We do know that most
• 47:23liver tumors receive their blood
• 47:24supply largely from the hepatic
• 47:26artery, and most liver tumors,
• 47:28including those of colorectal liver
• 47:30metastases,
• 47:31are often highly vascular.
• 47:33The goal is to selectively
• 47:34and locally deliver intra arterial
• 47:36therapeutics to the tumor bed.
• 47:38And by doing so, we
• 47:39can effectively target the tumor.
• 47:41We can spare surrounding hepatic
• 47:43parenchyma, and we can minimize
• 47:45systemic complications and toxicities.
• 47:47Now there's multiple different types
• 47:48of procedures that we can
• 47:50offer.
• 47:50Typically, they are done, through
• 47:52a
• 47:54a right sided,
• 47:55common femoral approach.
• 47:57It's just what we actually
• 47:59deliver. I don't have time
• 48:00to really go into all
• 48:01the details of the various,
• 48:03procedures that we can do,
• 48:04but we can say that
• 48:05we can do bland embolization,
• 48:07which is just a way
• 48:08of causing ischemia,
• 48:10and that just uses bland
• 48:11particles. We can do conventional
• 48:13taste where you mix chemotherapy
• 48:15with an oily substance called
• 48:17lapidol,
• 48:18which, can be infused into
• 48:20the tumor. We can do
• 48:21drug eluting b taste,
• 48:23which,
• 48:24is similar
• 48:25in in that, it's
• 48:27it's used to chemotherapy,
• 48:28but it's where,
• 48:30chemotherapy
• 48:31is infused into these beads,
• 48:33and then these beads will
• 48:34then be delivered to the
• 48:35tumor. And then, of course,
• 48:37we have, radioembolization
• 48:39where we can then deliver,
• 48:41specific amounts of radiation to
• 48:43either the tumor, locally
• 48:45or to a region.
• 48:48We also can do preoperative
• 48:49liver augmentation.
• 48:51You kind of heard about
• 48:51this a little bit. We
• 48:52can do portal and,
• 48:55hepatic vein embolization as well.
• 48:57The goal here is to
• 48:58redirect portal blood flow to
• 48:59the future liver remnant, and
• 49:01by doing so, initiate hypertrophy
• 49:03of the nonembolized
• 49:04segment.
• 49:05And by doing this, we
• 49:06can reduce the overall number
• 49:07of, perioperative complications.
• 49:11This would then lead to
• 49:12increasing the number of potential
• 49:14surgical candidates who have what
• 49:15we call marginal anticipated future
• 49:18liver remnant volumes,
• 49:19And previous studies have suggested
• 49:21that in order to reduce
• 49:23the morbidity of hepatic resection,
• 49:24about twenty percent of the
• 49:26liver must remain in patients
• 49:27with normal liver. That's patients
• 49:29that have never been pretreated
• 49:30with any kind of chemotherapy
• 49:31or radiation or anything.
• 49:33Thirty percent in injured liver,
• 49:35and we would say maybe
• 49:36patients that have high, high
• 49:38dose chemotherapy or steatohepatitis,
• 49:40and then forty percent in
• 49:42patients with, maybe cirrhosis
• 49:44with the goal of achieving
• 49:46what we would say is
• 49:47similar
• 49:48survival rates to cert to
• 49:49patients that did not actually
• 49:51require
• 49:51PVE
• 49:52prior to surgery.
• 49:55And just to give you
• 49:55some basic examples,
• 49:57this is a patient that,
• 49:59has a isolated liver metastases.
• 50:01We placed a needle,
• 50:03for ablation. I think in
• 50:04this case, we used a
• 50:06microwave,
• 50:07and you can see at
• 50:08one year follow-up,
• 50:09there is no tumor. So
• 50:10we can use high levels
• 50:12of,
• 50:13of, of of heat. In
• 50:14this case, usually, we use
• 50:16about a hundred degrees, Celsius.
• 50:18Here we see an example
• 50:20of, what's called the radiation
• 50:21segmentectomy, and we can see
• 50:22a small tumor in segment
• 50:24two
• 50:24just abutting near the heart.
• 50:27In this case, we felt
• 50:28that,
• 50:29that that, tumor ablation with
• 50:31a mic with a needle
• 50:33would be very risky. So
• 50:34we gave, radiation directly to
• 50:36that area, and you can
• 50:37see on the six month
• 50:38post,
• 50:39treatment,
• 50:40excellent, results. And now you
• 50:42see a one point four
• 50:43centimeter necrotic tumor
• 50:45that, previously might not have
• 50:46been easily treated.
• 50:48This is, an example of
• 50:50drug eluting bead TACE in
• 50:52a patient with you see
• 50:53this large right,
• 50:55hepatic lesion.
• 50:57And after two sessions,
• 50:58you can see after two
• 50:59month after four months that
• 51:01most of the tumor,
• 51:02is necrotic.
• 51:05And then this is a
• 51:05standard case of transarterial therapy
• 51:08using y ninety
• 51:09where we have innumerable,
• 51:11liver metastases.
• 51:12And then after radiation, we
• 51:14can see, that that are
• 51:15hypermetabolic
• 51:16on PET. And after six
• 51:18months, we can see
• 51:19a major reduction
• 51:21of, of these hypermetabolic
• 51:23metastases
• 51:24relative to, the pretreatment,
• 51:27you know, SPECT CT.
• 51:30This is a case, similar
• 51:31to what Saj
• 51:33Khan had shown, however, probably
• 51:35much worse. We would probably
• 51:36all say that the image
• 51:38the images on the left
• 51:39upper quadrant,
• 51:41would show that this patient
• 51:42is completely unresectable.
• 51:43K? And this patient ultimately
• 51:45underwent,
• 51:46preoperative chemotherapy.
• 51:48We found that his liver
• 51:49remnant, if had if they
• 51:50had surgery, is only sixteen
• 51:52percent. And as we said,
• 51:53this patient would need at
• 51:54least twenty percent. So we
• 51:56did a portal vein embolization
• 51:58through the liver,
• 52:00and then ultimately, the patient
• 52:02underwent their second stage
• 52:03and then ultimately had, I
• 52:05guess, what you would consider,
• 52:06a cure, in this in
• 52:08this case. So we were
• 52:09able to take a patient
• 52:10using,
• 52:11chemotherapy
• 52:12and neoadjuvant
• 52:13portal vein embolization and get
• 52:15a patient that was completely
• 52:17unresectable
• 52:18to successful resection. So this
• 52:20is something that I think,
• 52:22has really changed as a
• 52:23paradigm.
• 52:25Now just to show you
• 52:26all the data, I have
• 52:27a lot of data coming
• 52:28up. This is the results
• 52:30of portal vein embolization and
• 52:31its impact on major liver
• 52:33resection.
• 52:34This was a meta analysis,
• 52:35which included thirty seven publications,
• 52:38over one thousand patients,
• 52:40And you can see in
• 52:41terms of key data that
• 52:43PVE has been found to
• 52:44be safe and effective,
• 52:46k, with very low morbidity,
• 52:49and, there was actually no
• 52:50mortality
• 52:51in looking at those patients
• 52:52that underwent portal vein embolization.
• 52:54The patients did have an
• 52:56eighty five percent conversion rate
• 52:57surgery and there was no
• 52:59and there's very small,
• 53:01evidence of, post hepatectomy,
• 53:04liver failure.
• 53:06These were just some key
• 53:07studies I wanted to highlight.
• 53:09The first ones,
• 53:11from the early two thousands
• 53:12were just the early experience,
• 53:14and we were able to
• 53:15get five year overall survival
• 53:17of thirty seven to forty
• 53:18percent after resection. Now you
• 53:19have to remember that these
• 53:20patients would not have gotten
• 53:22resection without the PVE,
• 53:23so their five year overall
• 53:25survival would have been much
• 53:26worse.
• 53:27The second study that was
• 53:28published in, JCO,
• 53:30that showed that, in the
• 53:32use of, a two stage
• 53:34hepatectomy, which included portal vein
• 53:35embolization,
• 53:36it was very important to
• 53:38complete the second stage. And
• 53:39when the second stage was
• 53:40completed,
• 53:41we were able to achieve
• 53:42a fifty percent five year
• 53:43overall survival, which at that
• 53:45time was considered pretty amazing.
• 53:49We also looked at, those
• 53:50patients that did have high
• 53:52dose chemotherapy and the number
• 53:53of cycles. It was found
• 53:55that in those patients that
• 53:56had at least twelve weeks
• 53:57of chemotherapy preoperatively,
• 53:59that thirty percent that thirty
• 54:01percent of the liver remnant
• 54:02would be required to get
• 54:04patients through their resection.
• 54:06And then we're looking now
• 54:08at portal vein embolization versus,
• 54:11liver venous deprivation, which is
• 54:13adding hepatic vein embolization
• 54:14to it. And in this
• 54:15case, we can see that
• 54:17we were able to, increase
• 54:19the hypertrophy
• 54:20and get patients to surgery
• 54:22faster
• 54:23using this combined technique.
• 54:25Now we don't know if
• 54:26this is clinically relevant, but
• 54:27at this time, we're considering
• 54:29that it is. And most
• 54:31patients,
• 54:32get both procedures.
• 54:34They're all done at the
• 54:35same time. And, we're now
• 54:37gonna be doing a Dragon
• 54:38study that, we're part of
• 54:40the Dragon Consortium as well.
• 54:42And that will show that,
• 54:43hopefully, that this does work
• 54:45and does have benefit for,
• 54:47patients with bilateral colorectal living
• 54:49metastases.
• 54:50Now looking at local therapy,
• 54:52which in this case includes,
• 54:55ablation
• 54:56and, limited resection,
• 54:58we see that in this
• 54:59study that was the CLOCK,
• 55:02trial,
• 55:03it was systemic therapy alone
• 55:05versus systemic therapy plus aggressive
• 55:08local treatment. You can see
• 55:09that, this was,
• 55:11there was actually overall survival
• 55:13benefit,
• 55:14thirty six percent to nine
• 55:15percent in eight years. And
• 55:17I think, doctor Khan had
• 55:18shown that to us a
• 55:19little earlier. And that was,
• 55:20like, the first randomized study
• 55:22to show that.
• 55:23More recently, the collision trial
• 55:25was published.
• 55:27Doctor Khan briefly alluded to
• 55:29that too. This was a
• 55:30multicenter
• 55:31randomized clinical trial,
• 55:32which was,
• 55:34done
• 55:35in three hundred patients, looking
• 55:37at those patients that had,
• 55:39less than ten colorectal liver
• 55:40metastases,
• 55:41less than three centimeters.
• 55:43And,
• 55:44they were randomized one to
• 55:45one to ablation or resection,
• 55:46and you can see the
• 55:47data
• 55:48is, pretty impressive. Now this
• 55:50was done as a non
• 55:51inferior trial, not a superiority
• 55:54trial.
• 55:55So when we look at
• 55:56the data, you can see
• 55:57that the in terms of
• 55:58adverse events, serious adverse events,
• 56:00and mortality
• 56:02that there is a role
• 56:03for thermal ablation. And in
• 56:05fact,
• 56:06the trial was stopped at
• 56:07the halfway point for meeting
• 56:09all the stopping rules. And
• 56:10therefore,
• 56:11while,
• 56:12doctor Khan did say that
• 56:13surgery
• 56:14may be the preferred approach,
• 56:17We really need to individualize
• 56:19these patients to see if,
• 56:21colorectal cancer liver metastases may
• 56:23be better in certain patients
• 56:24being treated with ablation. And
• 56:26I can tell you that
• 56:27based on this trial,
• 56:28I have seen an uptick
• 56:30in our number of patients
• 56:31that are being treated with
• 56:32ablation
• 56:33for,
• 56:34colorectal liver metastases.
• 56:37Now getting on to conventional
• 56:39taste, there's only a couple
• 56:40of studies that show this.
• 56:41The idea here is that,
• 56:43these patients were refractory
• 56:45to systemic therapy,
• 56:46and they really had no
• 56:48other option.
• 56:49I would say that,
• 56:50in this, particular prospective,
• 56:53single center, single arm trial,
• 56:55the conventional taste did achieve
• 56:57meaningful disease control. And what
• 56:59I mean by that is
• 57:00in sixty three percent, patients
• 57:02did have a response.
• 57:04So this is a palliative
• 57:05strategy
• 57:06and, has, as you can
• 57:08see, has, been involved in
• 57:10prolonging life.
• 57:11The one year survival in
• 57:13these patients
• 57:15after,
• 57:15embolization
• 57:16was sixty two percent and
• 57:18two year survival
• 57:19was twenty eight percent. And
• 57:21this was just a retrospective
• 57:22study looking at a similar
• 57:24patient cohort
• 57:25in a hundred and twenty
• 57:26one patients with two hundred
• 57:28and forty five,
• 57:29treatments, and they also found
• 57:31that they got in conventional
• 57:32taste, moderate disease control. And
• 57:34they're this is done at
• 57:35University of Pennsylvania.
• 57:37And, in about forty percent
• 57:38of patients, they did have
• 57:40the this disease,
• 57:41control.
• 57:43Now in terms of, drug
• 57:45eluting beads,
• 57:46these are just some of
• 57:47the key studies.
• 57:49We, it does have a
• 57:51very different toxicity
• 57:52profile,
• 57:54because you're not using,
• 57:55systemic you're not getting a
• 57:57systemic toxicity,
• 57:59and there will be, shown
• 58:00quality of life advantages,
• 58:02favoring Dabirri. Now the two
• 58:04that I bolded, we're gonna
• 58:05discuss in a little more
• 58:06detail because those are the
• 58:08only two phase three prospective
• 58:10clinical trials
• 58:11that are available.
• 58:13Now this was the first
• 58:15one,
• 58:15published from, Italy,
• 58:18which compared Dabiri
• 58:20versus
• 58:20systemic therapy
• 58:22in patients who failed at
• 58:23least two lines of systemic
• 58:25therapy, including FOLFIRI.
• 58:27And we can see that
• 58:28in terms of the outcomes
• 58:30that,
• 58:31patients had overall survival of
• 58:33twenty two months versus,
• 58:35fifteen months for FOLFIRI.
• 58:37And in terms of, progression
• 58:38free survival,
• 58:39seven months to four months,
• 58:41which, as you can see,
• 58:42was, statistically,
• 58:44significant.
• 58:45And then the second,
• 58:47clinical trial I wanted to
• 58:48highlight is this one here,
• 58:50which was,
• 58:51the main, site was, I
• 58:53guess, University of of Louisville.
• 58:55And they found that the
• 58:56addition of Deburi
• 58:57significantly
• 58:58improved,
• 58:59response rate and progression free
• 59:01survival
• 59:02and did have a higher
• 59:03rate of conversion,
• 59:05to resection.
• 59:06So these patients had,
• 59:08despite
• 59:09worse baseline characteristics in the
• 59:11deveri arm, actually,
• 59:13had really good outcomes relative
• 59:15to, systemic therapy.
• 59:17And then lastly,
• 59:18these are the two main
• 59:20clinical trials,
• 59:22for y ninety.
• 59:23We have Servlox
• 59:25and EPoC. Now Servlox,
• 59:27also its sister, our companion
• 59:29study,
• 59:30FOXFIRE,
• 59:32were both, phase three,
• 59:34clinical trials.
• 59:36Servlox
• 59:37was
• 59:38with
• 59:40Siroflox and Foxfire
• 59:41are,
• 59:42first line treatments. We're we're,
• 59:45looking at first line treatments,
• 59:46and they used the product
• 59:48SIRSPHERE,
• 59:48whereas EPOC
• 59:50was,
• 59:51done
• 59:52as,
• 59:53second line therapy.
• 59:55And they use a completely
• 59:56different product which is TheraSPHERE.
• 59:58So although a lot of
• 59:59people will will just think
• 01:00:01that these two are interchangeable,
• 01:00:03they're actually really not. But,
• 01:00:05this is actually the, the
• 01:00:06baseline,
• 01:00:07I say we say clinical
• 01:00:08trials that show the benefits
• 01:00:10of y ninety.
• 01:00:12So here, I just want
• 01:00:13to isolate surfolox and FOXFRIO
• 01:00:15global.
• 01:00:16We can see that, the
• 01:00:18median overall survival and the
• 01:00:19progression free survival really didn't
• 01:00:21change, but we did see,
• 01:00:23in terms of liver specific
• 01:00:24progression free survival,
• 01:00:26improvement in both.
• 01:00:28It is important that a
• 01:00:29subgroup,
• 01:00:30analysis was done, which found
• 01:00:32that, there was improved survival
• 01:00:35benefit with y ninety in
• 01:00:37the setting of those patients
• 01:00:38that had right sided primary
• 01:00:39tumors.
• 01:00:40And, doctor Kormansky earlier had
• 01:00:42mentioned, why those patients actually
• 01:00:44have poor prognosis,
• 01:00:47with systemic therapy.
• 01:00:50This is the EPOC trial,
• 01:00:52again, which was, four hundred
• 01:00:54and twenty eight patients who
• 01:00:55had already progressed on oxaliplatin
• 01:00:58or arinoTPM based first line
• 01:00:59therapy. They were randomly assigned
• 01:01:02to either, second line chemotherapy
• 01:01:05with or without, radioembolization.
• 01:01:07And, again, we can see
• 01:01:09that in terms of, median
• 01:01:10progression free survival as well
• 01:01:12as hepatic progression free survival
• 01:01:14and response rate
• 01:01:16that, it was actually better
• 01:01:18with the the y ninety
• 01:01:20edition.
• 01:01:21And then they did a
• 01:01:22post hoc analysis
• 01:01:24where they looked at a
• 01:01:24subgroup of patients that excluded
• 01:01:26those patients that were ECOG
• 01:01:28one or who had worse,
• 01:01:30tumor burden
• 01:01:31and subgroup two, which they
• 01:01:33then looked at those patients
• 01:01:34that had KRAS mutations in
• 01:01:36addition to those in subgroup,
• 01:01:38in in the first subgroup.
• 01:01:39And they found that, ultimately,
• 01:01:42the benefit of y ninety
• 01:01:43is not uniform and that
• 01:01:45the greatest benefit is in
• 01:01:46patients with who already have
• 01:01:48good performance status of, primarily
• 01:01:51ECOG zero, lower tumor burden,
• 01:01:53and those that are KRAS
• 01:01:54wild type.
• 01:01:55And then lastly,
• 01:01:57when should these various envelope
• 01:01:58therapies be used? Now I
• 01:02:00put, based on a lot
• 01:02:01of the literature, a methodology
• 01:02:03of or rationale of how
• 01:02:05you would do this. The
• 01:02:06treatment selection is driven by,
• 01:02:09intent,
• 01:02:10tumor burden, and biology, and
• 01:02:12I you know, what I
• 01:02:13would say is that,
• 01:02:15a lot of this is
• 01:02:15also due to,
• 01:02:18I guess, ex expertise at
• 01:02:20various locations.
• 01:02:21So, I don't think there's
• 01:02:23really a great way to
• 01:02:24say this patient should get
• 01:02:25Deburi, this patient should get
• 01:02:27y ninety, or this patient
• 01:02:28should get conventional taste, but
• 01:02:29I can tell you that
• 01:02:30y ninety at this time
• 01:02:32is, is, is the treatment
• 01:02:34that's favored.
• 01:02:35So with that, I'll conclude,
• 01:02:38with stating that we all
• 01:02:39know that,
• 01:02:40colorectal liver metastases is a
• 01:02:42major problem.
• 01:02:43Multiple,
• 01:02:44patients ultimately are not resectable
• 01:02:46at the time of presentation.
• 01:02:48We know that liver metastases
• 01:02:50does represent the major cause
• 01:02:51of colorectal,
• 01:02:52mortality,
• 01:02:54and that using some of
• 01:02:55these inter interventional oncology strategies
• 01:02:57does expand the treatment options
• 01:03:00across the disease spectrum. And
• 01:03:01we can use, you know,
• 01:03:02preoperative augmentation
• 01:03:03for surgery. We can use
• 01:03:05ablation,
• 01:03:06and we can also use
• 01:03:07a transarterial therapy to control,
• 01:03:09liver dominant disease.
• 01:03:11And, hopefully, I've kind of
• 01:03:12relayed that,
• 01:03:14there is strong evidence to
• 01:03:15support these techniques,
• 01:03:16but we, again, have to
• 01:03:18use these, multidisciplinary,
• 01:03:21systems to best, handle our
• 01:03:23patients.
• 01:03:24So with that, I think
• 01:03:25I'll stop there and, thank
• 01:03:26you for your attention.
• 01:03:30Alright. Thank you, doctor Adolf.
• 01:03:33I think anything that's named
• 01:03:35Firefox
• 01:03:36sounds like an exciting therapy.
• 01:03:38Yeah. Sounds pretty cool.
• 01:03:41Alright. So, again, if anybody,
• 01:03:44has,
• 01:03:45questions for,
• 01:03:46any of the panelists, feel
• 01:03:48free to either enter them
• 01:03:50in the chat,
• 01:03:51or in the q and
• 01:03:53a,
• 01:03:54and we will,
• 01:03:55try to answer them as
• 01:03:56we go or,
• 01:03:59you know, at the end
• 01:04:00of the the session.
• 01:04:02We have one more,
• 01:04:04talk,
• 01:04:05on the role of radiation
• 01:04:07oncology in the treatment of,
• 01:04:09liver metastases,
• 01:04:11presented by doctor Du.
• 01:04:33Doctor Du, you're muted.
• 01:04:40Thank you. I coulda you
• 01:04:41coulda just let me go
• 01:04:42on for the rest of
• 01:04:43the talk.
• 01:04:44That would have been probably
• 01:04:45better.
• 01:04:47So I was saying, I
• 01:04:48think that this Thank you,
• 01:04:49Doctor. Karmansky. Thank you, everyone.
• 01:04:51This is really
• 01:04:53what I take home from
• 01:04:54this session is really this
• 01:04:56idea that we have a
• 01:04:57wealth of treatment options for
• 01:05:00colorectal
• 01:05:01liver metastases.
• 01:05:02And
• 01:05:03this is really a whirlwind
• 01:05:04tour tonight. So I'll talk
• 01:05:05to you about, the radiation
• 01:05:07part of it.
• 01:05:08Again, my name is Kevin
• 01:05:09Du. I'm associate professor in
• 01:05:10radiation oncology,
• 01:05:12at the Yale School of
• 01:05:13Medicine.
• 01:05:14And,
• 01:05:15I'll talk a little bit
• 01:05:16about radiation oncology,
• 01:05:19just because, radiation does tend
• 01:05:21to be a black box
• 01:05:22for many people, and then,
• 01:05:24specifically,
• 01:05:25what we can do with
• 01:05:26SBRT and liver metastases
• 01:05:28and then future opportunities
• 01:05:30that we have here at
• 01:05:30Yale.
• 01:05:32So, again, I'll just echo
• 01:05:34what everyone's been saying, which
• 01:05:35is this is an amazing
• 01:05:36group at Yale. GI oncology
• 01:05:38is inherently collaborative. It's a
• 01:05:40team effort, and, we have
• 01:05:42really a really amazing team
• 01:05:43here as tonight has demonstrated.
• 01:05:46Modern radiation therapy, I would
• 01:05:48say, is all about, the
• 01:05:49combining
• 01:05:50of all the advances in
• 01:05:52physics and biology that we've
• 01:05:53accumulated in the past century
• 01:05:56and really, using technology
• 01:05:58and advanced computing power to
• 01:06:00separate out the therapeutic index
• 01:06:02of, trying to control tumors
• 01:06:04while trying to spare normal
• 01:06:05tissues.
• 01:06:06And really, the overarching theme
• 01:06:07of radiation oncology is really
• 01:06:09this idea of, functional preservation,
• 01:06:11organ preservation,
• 01:06:14instead of the paradigm to
• 01:06:15cut is to cure.
• 01:06:17No offense, doctor Khan.
• 01:06:19Really, using radiation,
• 01:06:21to try to,
• 01:06:24save,
• 01:06:26organs. And, and then the
• 01:06:28idea of, how do we,
• 01:06:30maximize tumor response, get,
• 01:06:32real, meaningful, and deep,
• 01:06:35control of cancers.
• 01:06:38So this is our workhorse
• 01:06:39machine.
• 01:06:40We call them linear accelerators
• 01:06:42or LINACs.
• 01:06:43They're all we do is
• 01:06:45we aim and focus and
• 01:06:46shape
• 01:06:47radiation, using x rays
• 01:06:49and, aiming the x rays
• 01:06:50at the tumor. This is
• 01:06:52a noninvasive
• 01:06:53treatment.
• 01:06:54No anesthesia,
• 01:06:56no,
• 01:06:57sedation.
• 01:06:58This entirely outpatient. You come
• 01:07:00in, you get the treatment,
• 01:07:02you go home, you can
• 01:07:03drive yourself,
• 01:07:04and it's a painless treatment,
• 01:07:05laying there on the treatment
• 01:07:07machine just like any other
• 01:07:08x-ray.
• 01:07:10We have
• 01:07:12striven to,
• 01:07:14to,
• 01:07:15to try to make radiation
• 01:07:16more convenient and effective. And,
• 01:07:18this is really where, for
• 01:07:20liver, we've gone from very
• 01:07:22long extended multi week courses,
• 01:07:24many times five, six, seven,
• 01:07:26eight weeks of radiation
• 01:07:28daily to really,
• 01:07:30high doses of radiation to
• 01:07:32small,
• 01:07:34to small areas,
• 01:07:36a technique called stereotactic
• 01:07:38radiation therapy or SBRT
• 01:07:40for short.
• 01:07:41And, this is the idea
• 01:07:43that instead of treating a
• 01:07:44whole organ,
• 01:07:45here we see, like, for
• 01:07:47example, an example of whole
• 01:07:48brain radiation,
• 01:07:50really,
• 01:07:51treating very focused areas. You
• 01:07:53can see these little colored
• 01:07:55spots where we're really focusing
• 01:07:56the radiations,
• 01:07:58and,
• 01:07:59and really, trying to get
• 01:08:00very high ablative doses to
• 01:08:02provide long term control.
• 01:08:04So, this is start this
• 01:08:05paradigm started off in the
• 01:08:07brain as I'm showing you
• 01:08:09and has expanded across multiple
• 01:08:10body sites, including the spine,
• 01:08:13lung
• 01:08:14early stage lung cancers,
• 01:08:16and, even getting into GI,
• 01:08:19oncology,
• 01:08:20the GI oncology space such
• 01:08:22as in pancreas cancers.
• 01:08:24And, in all of these,
• 01:08:25the idea is really to
• 01:08:27try to,
• 01:08:29provide a treatment,
• 01:08:32that's effective,
• 01:08:34for and, that's well tolerated,
• 01:08:36and and that in in
• 01:08:38many cases may be better
• 01:08:39tolerated than, surgical interventions.
• 01:08:43So,
• 01:08:44for liver,
• 01:08:45we this is a a
• 01:08:47a newer approach. And by
• 01:08:48new, I mean that we've
• 01:08:50really been doing it for
• 01:08:50twenty years, but in medicine,
• 01:08:52that's considered new.
• 01:08:54This is,
• 01:08:55where we focus radiation at
• 01:08:57liver tumors. So this is,
• 01:09:00where we're defining our target
• 01:09:01area in the red, and,
• 01:09:03the red,
• 01:09:05blue, green color wash is
• 01:09:08really this,
• 01:09:09is this, this kind of
• 01:09:10dose distribution of a highly
• 01:09:12focused radiation
• 01:09:14dose at the tumor, but
• 01:09:16then lower dose,
• 01:09:18around where we're focusing the
• 01:09:20radiation. And the analogy is
• 01:09:21like spotlights on a stage
• 01:09:23where there's a focused hot
• 01:09:24spot, but there's kind of
• 01:09:25this low dose bath of
• 01:09:27lights across,
• 01:09:28the stage.
• 01:09:29And, we can really treat
• 01:09:31rate, very effectively with this
• 01:09:33high dose radiation. And, you
• 01:09:35can see here the treatment
• 01:09:36effect where you have, hemorrhage,
• 01:09:42vascular
• 01:09:43fibrosis,
• 01:09:44and, tumor death.
• 01:09:46And, it's nice because, with
• 01:09:48three-dimensional
• 01:09:49imaging, we can see the
• 01:09:51anatomy
• 01:09:52in real time, and we
• 01:09:53can actually modulate the dose
• 01:09:55to affect
• 01:09:56critical organs at risk like
• 01:09:58the bowel, which in this
• 01:09:59case is right next to
• 01:10:01our target, and modulate it
• 01:10:03and and really aim very
• 01:10:04carefully so that we're safe
• 01:10:05about this treatment.
• 01:10:07And,
• 01:10:08and,
• 01:10:09and and this has been,
• 01:10:12you know, over the years,
• 01:10:15becoming more and more,
• 01:10:17I I would say safe
• 01:10:19as we learn,
• 01:10:20more and get more experience
• 01:10:22in our field.
• 01:10:23And so, these days, we're
• 01:10:25very careful about it in
• 01:10:26terms of trying to, maximize
• 01:10:28the tumor coverage, but then
• 01:10:29avoiding the normal tissue risks.
• 01:10:31And, this is an example
• 01:10:33of, some of the schematics
• 01:10:35that show our dose distribution
• 01:10:37to the tumor,
• 01:10:38compared to normal tissue. And,
• 01:10:40you know, basically, farther over
• 01:10:42to the right is, better
• 01:10:44coverage, and farther over to
• 01:10:46left is better normal tissue
• 01:10:48sparing. And you can see
• 01:10:49the really wide separation in
• 01:10:50the curves there.
• 01:10:52So this is an example.
• 01:10:53One of my patients situated
• 01:10:54a few years ago,
• 01:10:57did a dose of SBRT
• 01:10:59here, relatively low dose, forty
• 01:11:01gram and five fractions.
• 01:11:03Maybe not low dose, modest
• 01:11:04dose.
• 01:11:05This is a tumor that's
• 01:11:07really at the inferior liver
• 01:11:08surrounded by bowel, the kidney.
• 01:11:11And you can see right
• 01:11:12after treatment of this liver
• 01:11:13lesion,
• 01:11:15shrinkage over the course of
• 01:11:16the following ten months, and
• 01:11:18this has since been very
• 01:11:19well controlled.
• 01:11:21This is a fifty five
• 01:11:23year old woman with a
• 01:11:24single, solitary liver metastases.
• 01:11:27Very small favorable, not anywhere
• 01:11:29near bowel. We're able to
• 01:11:30go to a full ablative
• 01:11:31dose of fifty gram five
• 01:11:33fractions
• 01:11:34and really, very well controlled
• 01:11:36here as seen in this
• 01:11:37PET scan response.
• 01:11:39And,
• 01:11:40going past, sort of case
• 01:11:42reports,
• 01:11:43we have,
• 01:11:45some, I would say, emerging
• 01:11:48data, to support the use
• 01:11:50of SBRT for liver metastases.
• 01:11:52This is out of,
• 01:11:55the, the Netherlands
• 01:11:57and,
• 01:11:58you know, kind of a
• 01:11:59little bit outdated at this
• 01:12:00point, twenty thirteen to twenty
• 01:12:02nineteen era,
• 01:12:04about five hundred patients over
• 01:12:05thirteen centers, eighty percent of
• 01:12:07these were actually colorectal metastases.
• 01:12:10Overall, local control about
• 01:12:12one year about eighty seven
• 01:12:13percent, and then this went
• 01:12:15down to seventy five percent
• 01:12:16over two years.
• 01:12:17Very encouragingly, phase,
• 01:12:19grade three four toxicities, only
• 01:12:21about four percent. So very
• 01:12:23low,
• 01:12:24grade three four toxicities.
• 01:12:26Phase two trial out of,
• 01:12:28Milan,
• 01:12:30sixty one patients, small small
• 01:12:32small trial, but,
• 01:12:35over one, three, and five
• 01:12:37years local control rates of
• 01:12:38ninety five percent and then
• 01:12:40really stabilizing and plateauing around
• 01:12:43eighty percent local control up
• 01:12:44to five years.
• 01:12:46Only one patient with a
• 01:12:47grade three adverse events, which
• 01:12:50was,
• 01:12:51chest wall pain, which can
• 01:12:52happen when the lesion is
• 01:12:54too close to the chest
• 01:12:55wall and causes some,
• 01:12:57inflammation
• 01:12:58or fibrosis.
• 01:13:00However, this chest wall pain
• 01:13:01resolved within a year, which
• 01:13:03we might expect actually to
• 01:13:05see with with patients after
• 01:13:07radiation,
• 01:13:09and,
• 01:13:10no,
• 01:13:11inflammation of the liver, which
• 01:13:12is, nice to see.
• 01:13:14And then,
• 01:13:15SBRT
• 01:13:16s g zero one rolls
• 01:13:18off the tongue. This is
• 01:13:19a prospective study. Again, kind
• 01:13:21of a little outdated, just
• 01:13:23starting over a decade ago
• 01:13:24now, but fifty patients,
• 01:13:26medium follow-up about two years.
• 01:13:28And the two to four
• 01:13:29year local control is about
• 01:13:30eighty five percent, and then,
• 01:13:32again, kind of plateauing around
• 01:13:33eighty percent.
• 01:13:35And,
• 01:13:36interestingly,
• 01:13:37as you can see here,
• 01:13:39on the left sorry, on
• 01:13:41the right, is that patients
• 01:13:42with smaller tumors, less than
• 01:13:43five centimeter tumors, had much
• 01:13:45better progression free survival.
• 01:13:47And so this does go
• 01:13:49to sort of the point
• 01:13:50that, many times,
• 01:13:54you know, when patients have
• 01:13:55favorable small tumors
• 01:13:57that,
• 01:13:58really, those are the ones
• 01:14:00we have the most success
• 01:14:01with.
• 01:14:02So over overall, you know,
• 01:14:05combining
• 01:14:06many studies, thirty three studies,
• 01:14:08three thousand patients from the
• 01:14:10nineties to twenty twenties,
• 01:14:13most of these retrospective series,
• 01:14:15five perspective series in this
• 01:14:16meta analysis,
• 01:14:18that,
• 01:14:19with about fifty percent of
• 01:14:21patients,
• 01:14:23who've
• 01:14:24in this series who have
• 01:14:25colorectal cancer,
• 01:14:28maybe sounding starting to sound
• 01:14:30like a broken record, but,
• 01:14:31local control at one year
• 01:14:32about eighty five percent and
• 01:14:34then kind of,
• 01:14:35two, three year going down
• 01:14:37a little bit.
• 01:14:39Encouraging,
• 01:14:40again, very safe treatment,
• 01:14:42greater than grade three side
• 01:14:44effects, only three percent in
• 01:14:46over thirty thousand patients.
• 01:14:50And, you know, just a
• 01:14:51nod to doctor Madoff,
• 01:14:52that, you know, we are,
• 01:14:55we are,
• 01:14:57just like I'm following doctor
• 01:14:58Madoff, maybe SBRT is following
• 01:15:00ablation.
• 01:15:02The Amsterdam core registry,
• 01:15:04compared
• 01:15:06patients that had ablation to
• 01:15:08patients that had SBRT, small
• 01:15:09series, only one hundred and
• 01:15:10forty four patients who had
• 01:15:12ablation,
• 01:15:13and versus fifty five patients,
• 01:15:15very small series, who had
• 01:15:16SBRT. And again, this is
• 01:15:18not a clinical trial, this
• 01:15:19is a registry.
• 01:15:21Patients who had SBRT were
• 01:15:22older, had more extra hepatic
• 01:15:24disease, larger tumors compared to
• 01:15:26the ablation patients.
• 01:15:28But,
• 01:15:29overall, the local progratitor free
• 01:15:31survival
• 01:15:32favored
• 01:15:33it was in favor of
• 01:15:34a better control with, ablation
• 01:15:36hazard ratio one point two
• 01:15:38four.
• 01:15:40Interestingly,
• 01:15:41in these patients, again, a
• 01:15:42small cohort,
• 01:15:43no SAEs with SBRT and
• 01:15:45about six percent to greater
• 01:15:47than, grade three,
• 01:15:49SAEs with ablation.
• 01:15:53So,
• 01:15:54overall,
• 01:15:55you know, the data is
• 01:15:56intriguing,
• 01:15:57but, at the same time,
• 01:15:59I, you know, I I
• 01:16:01I I would,
• 01:16:03always,
• 01:16:05say that,
• 01:16:06SBRT is an option, but
• 01:16:07it's, unclear,
• 01:16:09you know, especially for patients
• 01:16:11with small favorable,
• 01:16:13tumors. You know, surgery,
• 01:16:16is is still the gold
• 01:16:17standard. Ablation is still,
• 01:16:19more,
• 01:16:20commonly done. And so, this
• 01:16:22is the
• 01:16:24American Radium Society consensus guidelines
• 01:16:27for selection of local therapies,
• 01:16:29for,
• 01:16:30for liver metastases published a
• 01:16:32few years ago. And this
• 01:16:34is actually the the author
• 01:16:35line was was mostly all
• 01:16:37radoncs. And even then, you
• 01:16:39know, I think, even with
• 01:16:40that bias that these are
• 01:16:42actually radiation oncologists putting this
• 01:16:44together,
• 01:16:45they deferred,
• 01:16:47SBRT,
• 01:16:49for,
• 01:16:50and and kind of subset
• 01:16:51it out most patients, I
• 01:16:53think, that would be favorable
• 01:16:54for ablation.
• 01:16:55However, if,
• 01:16:57if the tumor was larger,
• 01:16:58probably,
• 01:16:59maybe leaning more toward SBRT.
• 01:17:03And,
• 01:17:04you know, but but, certainly,
• 01:17:07a multidisciplinary
• 01:17:08discussion in this,
• 01:17:09this this workflow kinda gives
• 01:17:11me a headache here.
• 01:17:14I think we, of course,
• 01:17:16then need
• 01:17:18stronger data to really try
• 01:17:20to figure out, the role
• 01:17:21of SBRT with all the
• 01:17:23other local regional therapies we
• 01:17:24use.
• 01:17:26The collision trial was,
• 01:17:28was discussed,
• 01:17:30looking at,
• 01:17:31ablation versus surgery.
• 01:17:33The collision group,
• 01:17:35started this collision XL trial
• 01:17:37phase two, three randomized controlled
• 01:17:39trial,
• 01:17:40patients with colorectal cancer liver
• 01:17:42metastases,
• 01:17:43looking at, microwave ablation versus
• 01:17:46SBRT, still enrolling, and I'm
• 01:17:48not entirely sure if it
• 01:17:50will complete, but,
• 01:17:52difficult trial to,
• 01:17:54to randomize to, but certainly
• 01:17:56something which, we need.
• 01:17:59So,
• 01:18:00so,
• 01:18:02so I think, you know,
• 01:18:03here at Yale then,
• 01:18:05just to kind of, say
• 01:18:07what we have,
• 01:18:08you know, we are moving
• 01:18:09toward MR guided radiation for
• 01:18:11liver SBRT.
• 01:18:12MRI imaging is just, so
• 01:18:15much better than CT based
• 01:18:17imaging for,
• 01:18:18targeting. And in this, trial
• 01:18:20looking at MR guided radiation,
• 01:18:23one year local control with
• 01:18:24ninety five percent and then
• 01:18:26two year kind of eighty
• 01:18:27percent range,
• 01:18:29very little
• 01:18:31toxicity.
• 01:18:32And here at Yale, we
• 01:18:33have two programs which are,
• 01:18:35up and coming.
• 01:18:36One is, this idea of
• 01:18:38pet guided
• 01:18:39biologic,
• 01:18:41radiation therapy.
• 01:18:43And,
• 01:18:43really, this idea of using
• 01:18:45PET guidance to target multiple
• 01:18:47spots,
• 01:18:48simultaneously
• 01:18:49with s an SBRT approach.
• 01:18:53This is, FDA approved for
• 01:18:55lung and bone,
• 01:18:57lesions,
• 01:18:58and, not yet for liver,
• 01:19:00but, I think would be
• 01:19:01an attractive approach and certainly,
• 01:19:04something we're interested in developing.
• 01:19:06And then, very importantly for
• 01:19:08the state of Connecticut, we
• 01:19:09have,
• 01:19:10the Connecticut Proton Sent Therapy
• 01:19:13Center opening up in Wallingford
• 01:19:15this coming October,
• 01:19:18ahead of schedule for opening,
• 01:19:20where
• 01:19:22proton therapy is a very
• 01:19:24valuable,
• 01:19:26and
• 01:19:27form of radiation
• 01:19:29where,
• 01:19:30that can potentially lead to,
• 01:19:32better organ sparing,
• 01:19:34normal tissue sparing, I should
• 01:19:35say, for radiation, reducing the
• 01:19:37toxicities,
• 01:19:38making radiation safer, and potentially
• 01:19:40allowing the
• 01:19:43ability to,
• 01:19:44to increase radiation dose and
• 01:19:46get a better therapeutic effect.
• 01:19:48So, this is something where,
• 01:19:51this is will be the
• 01:19:52first and and only,
• 01:19:54proton center in Connecticut and,
• 01:19:57something where, for liver directed
• 01:19:59therapy, this has been looked
• 01:20:00at,
• 01:20:02really in terms of, very
• 01:20:03great, very, very, much,
• 01:20:06much more effectively sparing normal
• 01:20:08liver from radiation exposure. And
• 01:20:11you can see that here
• 01:20:12with this kind of even
• 01:20:13though the the the red
• 01:20:15hot spot is is, very
• 01:20:17well shaped in both plans
• 01:20:19here on the left and
• 01:20:20a proton plan and here
• 01:20:21on the right,
• 01:20:22x-ray plan,
• 01:20:24that the low dose bath
• 01:20:25is greatly reduced,
• 01:20:27with, with protons,
• 01:20:28which can, really, help to
• 01:20:30reduce some of those,
• 01:20:33potential side effects of radiation.
• 01:20:35So
• 01:20:37ultimately, this is a non
• 01:20:39invasive
• 01:20:40technique. No an anesthesia,
• 01:20:42you know, probably,
• 01:20:44in the current paradigm,
• 01:20:46best for patients who,
• 01:20:48are not, really up for
• 01:20:50surgery
• 01:20:51or and may want to
• 01:20:53avoid procedures.
• 01:20:55The,
• 01:20:56one year local control rate
• 01:20:58is somewhere from eighty five
• 01:20:59to ninety five percent and
• 01:21:00then kind of levels off
• 01:21:02around eighty percent after that.
• 01:21:03So, you know, not as
• 01:21:04good as surgery, but,
• 01:21:06also less invasive.
• 01:21:08So, you know, patients may,
• 01:21:10think that maybe they wanna
• 01:21:11give it a try since
• 01:21:12there is a good control
• 01:21:13rate, if it avoids,
• 01:21:16a stay in the hospital.
• 01:21:18Low rates of,
• 01:21:20of, grade three adverse events.
• 01:21:22However,
• 01:21:24all the data is really
• 01:21:25kind of early and, or
• 01:21:27retrospective
• 01:21:28series
• 01:21:28and randomized clinical trials are
• 01:21:30really needed to compare what,
• 01:21:32what we're doing with radiation.
• 01:21:34And is it, better or
• 01:21:35worse than and and to
• 01:21:37what degree to other,
• 01:21:40available liver directed therapies of
• 01:21:42which there are many in
• 01:21:43which they are effective.
• 01:21:46And then there's the opportunity
• 01:21:47for programmatic developments and novel
• 01:21:49technologies at Yale,
• 01:21:51MR guided SBRT,
• 01:21:53PET guided SBRT, and very
• 01:21:54importantly,
• 01:21:55proton therapies.
• 01:21:57So, thank you very much
• 01:21:58for all your attention,
• 01:22:00and for the platform to,
• 01:22:02discuss
• 01:22:03radiation and the role of
• 01:22:04SBRT and liver colorectal metastases.
• 01:22:08I'll, turn it back over
• 01:22:09to doctor Kormansky.
• 01:22:13Alright. Well, we have reached
• 01:22:15the end of our talks.
• 01:22:17I wanna thank,
• 01:22:19my colleagues for their,
• 01:22:22excellent
• 01:22:23overviews. I know each of
• 01:22:24them could probably go on
• 01:22:26for hours on their individual
• 01:22:28topics.
• 01:22:29And so
• 01:22:31I also wanna
• 01:22:32point out that, you know,
• 01:22:33what is clear
• 01:22:35is that management of colorectal
• 01:22:38liver metastases in an aggressive
• 01:22:40fashion
• 01:22:41matters and can improve survival,
• 01:22:44and that doing that in
• 01:22:45a way that is,
• 01:22:47through a collaborative
• 01:22:48team,
• 01:22:49is really important.
• 01:22:51We do,
• 01:22:53have a couple of minutes
• 01:22:55for some questions. I think
• 01:22:56most of them have been
• 01:22:58answered as they came through
• 01:22:59in the chat, and I
• 01:23:00don't see any
• 01:23:02additional there.
• 01:23:04I did wanna point out
• 01:23:05one of the questions did,
• 01:23:08ask about,
• 01:23:09the role of,
• 01:23:11ctDNA
• 01:23:12in in monitoring,
• 01:23:14minimal residual disease, and I
• 01:23:16would say
• 01:23:17that that is a topic
• 01:23:19that can be its own,
• 01:23:22CME webinar at a future
• 01:23:24date. I think there's, you
• 01:23:25know, lots a lot that
• 01:23:26we know
• 01:23:27and probably even more that
• 01:23:29we don't know about how
• 01:23:30best to use that technology.
• 01:23:36Right. There is,
• 01:23:39one,
• 01:23:40question,
• 01:23:42for doctor Du,
• 01:23:45asking about the role of
• 01:23:47chemosensitizing
• 01:23:48drugs in the in the
• 01:23:49use of SBRT.
• 01:23:51Yeah. You caught me right
• 01:23:52as I was, trying to
• 01:23:53type an answer there, doctor
• 01:23:55Kromansky. So,
• 01:23:57I'll say that,
• 01:23:58this has been looked at
• 01:24:00with,
• 01:24:01SRS.
• 01:24:01I would say that's more
• 01:24:03brain directed,
• 01:24:06stereotactic treatment. But then also
• 01:24:09in some early phase,
• 01:24:11clinical trials for SBRT and
• 01:24:13other sites, you know, I
• 01:24:15ran a,
• 01:24:16a phase one trial a
• 01:24:17few years ago looking at
• 01:24:19immunotherapy combined with SBRT for
• 01:24:21pancreas cancers.
• 01:24:23And, you know, I've I've
• 01:24:24been seeing a lot of
• 01:24:25proposals
• 01:24:26for looking at, the combination
• 01:24:28of biologics like immunotherapy
• 01:24:30with SBRT
• 01:24:31for liver cancers. And in
• 01:24:33fact, we have not for,
• 01:24:35HCC, but for sorry. Not
• 01:24:37for colorectal metastases, but for
• 01:24:39HCC at this point, a,
• 01:24:41clinical trial that's a national
• 01:24:43cooperative group trial looking for
• 01:24:45HCC at the combination of
• 01:24:47immunotherapy with SBRT
• 01:24:49and trying to figure out
• 01:24:50if that's, more effective than
• 01:24:51immunotherapy alone.
• 01:24:54So, there's a lot of,
• 01:24:56I think work to be
• 01:24:57done there. At least we
• 01:24:59think that,
• 01:25:01because SBRT is such a
• 01:25:02focused,
• 01:25:03treatment that it's likely to
• 01:25:05be safe with many,
• 01:25:06systemic therapies,
• 01:25:08And there needs to be
• 01:25:09a lot more work to
• 01:25:11define the biology and the
• 01:25:13but the biologic interaction of,
• 01:25:15chemotherapies
• 01:25:16and other targeted biologic therapies,
• 01:25:20in combination with SBRT to
• 01:25:22try to improve effectiveness. But
• 01:25:23that's a great question
• 01:25:25and very important for clinical
• 01:25:26trial work.
• 01:25:30Right. Well, it looks like
• 01:25:31we're coming up on the
• 01:25:33hour.
• 01:25:34I wanna, again, thank our
• 01:25:35panelists. I also wanna thank
• 01:25:37our audience,
• 01:25:38for their attention and engagement,
• 01:25:42during this session. I hope
• 01:25:43it was,
• 01:25:45informative,
• 01:25:46and,
• 01:25:47know that all of us
• 01:25:50would be available for sidebars
• 01:25:52at a future time as
• 01:25:53needed.
• 01:25:55So I hope everybody has
• 01:25:57a great evening.
• 01:25:59Thanks so much. Thank you.